One embodiment of this invention relates to synthesis of olefins and, in particular, to stereospecific synthesis of tri- and tetra-substituted olefins.
The highly stereoselective construction of tri- and tetra-substituted olefins is currently one of the most challenging problems in synthetic organic chemistry. Tri- and tetra-substituted olefins are common structural units in almost every class of compounds, particularly natural products. Their synthesis is consequently of great importance to the pharmaceutical, agricultural, and fine chemical industries. However, there are few methods that can do this efficiently, economically, and with high stereoselectivity. Many extant procedures give poor yields, require expensive reagents, have inconvenient reaction conditions, produce undesirable by-products, and afford mixtures of isomers. Since the isomers and by-products may be hard to remove, impart undesirable chemical or physical properties, and have unwanted biological properties, these compounds must be separated by methods that can be costly, difficult to conduct on a large scale, and time consuming.
The literature provides some examples of methods for the synthesis of tri-substituted olefins. (See Tago et al., Organic Lett., 2:1975–78 (2000); Ishino et al., Bull. Chem. Soc. Jpn., 71:2669–72 (1998); Goumain et al., Synthesis, 6:984 (1999); and Kruper et al., J. Org. Chem., 56:3323–29 (1991)). In addition, some previous examples exist for the synthesis of tetra-substituted olefins, such as α-halo acrylates. (See Takai et al., Bull. Chem. Soc. Jpn., 53:1698–1702 (1980); Masahira et al., Synth. Commun., 30:863–68 (2000); Terent'ev et al., Russ. Chem. Bull., 48:1121–27 (1999)). However, these methods tend to be inefficient due to lack of stereoselectivity or the need for a multi-step procedure.
Most frequently, Wittig and Horner-Wadsworth-Emmons (“HWE”) reactions are used in the synthesis of various olefins. (See Wadsworth et al., Org. React., 25:73 (1977); Maryanoff et al., Chem. Rev., 89:863 (1989); and Vedejs et al., Top. Stereochem., 21:1 (1994)). But the construction of tri- and tetra-substituted alkenes is subject to the limitations of variable stereoselectivity, costly reagents, and low yields.